Combination therapy for treating abnormal cell growth

Abstract

The present invention relates to methods, compositions, and oral dosage forms of a SHP2 inhibitor, a SOS1 inhibitor, an ERK1/2 inhibitor, a CDK4/6 inhibitor, an AKT inhibitor, an mTOR inhibitor, a pan-HER inhibitor, or an EGFR inhibitor in combination with a MEK inhibitor or a dual RAF/MEK inhibitor, for treating abnormal cell growth (e.g., cancer).

1 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of a CDK4/6 inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject. 
     
     
         2 . The method of  claim 1 , wherein the CDK4/6 inhibitor is GLR2007, Roniciclib, RP-CDK4/6, TQB3303, Trilaciclib, SHR-6390, Lerociclib, FCN-437c, Milciclib, PF-06873600, XZP-3287, ON-123300, ETH-155008, HEC-80797, JS-104, PF-07220060, RMC-4550, SRX-3177, VS-2370), Palbociclib, Ribociclib, Letrozole+Ribociclib, or Abemaciclib, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1  or  2 , wherein the CDK4/6 inhibitor is Abemaciclib, Palbociclib, or Ribociclib, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the CDK4/6 inhibitor is administered at least once daily. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the CDK4/6 inhibitor is administered once daily. 
     
     
         6 . The method of any one of  claims 1 - 4 , wherein the CDK4/6 inhibitor is administered twice daily. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the CDK4/6 inhibitor is administered orally. 
     
     
         8 . The method of any one of  claims 1 - 7 , wherein the CDK4/6 inhibitor is dosed at about 1 mg to about 1000 mg per administration. 
     
     
         9 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of a SOS1 inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject. 
     
     
         10 . The method of  claim 9 , wherein the SOS1 inhibitor is BMS-SCH, SDGR5, BI-3406, BAY-293, RMC-5845, SDGR-5, or BI-1701963, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 9  or  10 , wherein the SOS1 inhibitor is SDGR-5, BI-3406, or B1-1701963, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of any one of  claims 9 - 11 , wherein the SOS1 inhibitor is administered at least once daily. 
     
     
         13 . The method of any one of  claims 9 - 12 , wherein the SOS1 inhibitor is administered once daily. 
     
     
         14 . The method of any one of  claims 9 - 12 , wherein the SOS1 inhibitor is administered twice daily. 
     
     
         15 . The method of any one of  claims 9 - 14 , wherein the SOS1 inhibitor is administered orally. 
     
     
         16 . The method of any one of  claims 9 - 15 , wherein the SOS1 inhibitor is dosed at about 1 mg to about 1000 mg per administration. 
     
     
         17 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an ERK1/2 inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject. 
     
     
         18 . The method of  claim 17 , wherein the ERK1/2 inhibitor is AZ6197, BI ERKi, CC-90003, ERAS-007, HMPL-295, IPN-ERK, KO-947, LTT462, SCH772984, TK216, ASTX-029, HH-2710, LY-3214996, ulixertinib, ASN-007, ATG-017, BPI-27336, JSI-1187, MK-8353, JRP-890, or JRF-108, or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 17  or  18 , wherein the ERK1/2 inhibitor is LY-3214996, or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of any one of  claims 17 - 19 , wherein the ERK1/2 inhibitor is administered at least once daily. 
     
     
         21 . The method of any one of  claims 17 - 20 , wherein the ERK1/2 inhibitor is administered once daily. 
     
     
         22 . The method of any one of  claims 17 - 20 , wherein the ERK1/2 inhibitor is administered twice daily. 
     
     
         23 . The method of any one of  claims 17 - 22 , wherein the ERK1/2 inhibitor is administered orally. 
     
     
         24 . The method of any one of  claims 17 - 23 , wherein the ERK1/2 inhibitor is dosed at about 1 mg to about 1000 mg per administration. 
     
     
         25 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of a SHP2 inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject. 
     
     
         26 . The method of  claim 25 , wherein the SHP2 inhibitor is ERAS-601, TNO-155, SHP099, RMC-4630, RMC-4550, IACS-13909, JAB-3068, JAB-3312, RLY-1971, BBP-398, HBI-2376, or ICP-189, BR790, ETS-001, PF-07284892, RX-SHP2i, SH3809, TAS-ASTX, X-37-SHP2, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method of  claim 25  or  26 , wherein the SHP2 inhibitor is JAB-3068, RMC-4630, TNO-155, JAB-3312, RLY-1971, BBP-398, HBI-2376, ICP-189, or RMC-4550, or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The method of any one of  claims 25 - 27 , wherein the SHP2 inhibitor is administered at least once daily. 
     
     
         29 . The method of any one of  claims 25 - 28 , wherein the SHP2 inhibitor is administered once daily. 
     
     
         30 . The method of any one of  claims 25 - 28 , wherein the SHP2 inhibitor is administered twice daily. 
     
     
         31 . The method of any one of  claims 25 - 30 , wherein the SHP2 inhibitor is administered orally. 
     
     
         32 . The method of any one of  claims 25 - 31 , wherein the SHP2 inhibitor is dosed at about 1 mg to about 1000 mg per administration. 
     
     
         33 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an AKT inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject. 
     
     
         34 . The method of  claim 33 , wherein the AKT inhibitor is capivasertib, ipatasertib, LY-2503029, afuresertib hydrochloride, COTI-2, miransertib mesylate, MK-2206, MK-2206+selumetinib sulfate, ONC-201, PTX-200, TAS-117, trametinib dimethyl sulfoxide+uprosertib, uprosertib, ARQ-751, AT-13148, M2698, ALM-301, BAY-1125976, borussertib, DC-120, FXY-1, JRP-890, KS-99, NISC-6, RX-0201, or RX-0301, or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 33  or  34 , wherein the AKT inhibitor is M2698 or ipatasertib, or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method of any one of  claims 33 - 35 , wherein the AKT inhibitor is administered at least once daily. 
     
     
         37 . The method of any one of  claims 33 - 36 , wherein the AKT inhibitor is administered once daily. 
     
     
         38 . The method of any one of  claims 33 - 36 , wherein the AKT inhibitor is administered twice daily. 
     
     
         39 . The method of any one of  claims 33 - 38 , wherein the AKT inhibitor is administered orally. 
     
     
         40 . The method of any one of  claims 33 - 39 , wherein the AKT inhibitor is dosed at about 1 mg to about 1000 mg per administration. 
     
     
         41 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an mTOR inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject. 
     
     
         42 . The method of  claim 41 , wherein the mTOR inhibitor is everolimus, zortress, sirolimus, temsirolimus, sirolimus albumin-bound, dactolisib tosylate, onatasertib, DTRMWXHS-12+everolimus+pomalidomide, bimiralisib, CC-115, monepantel, sapanisertib, sirolimus, vistusertib, detorsertib, FP-208, HEC-68498, LXI-15029, ME-344, PTX-367, WXFL-10030390, XP-105, paclitaxel+sirolimus+tanespimycin, AL-58805, AL-58922, AUM-302, CA-102, CA-103, CT-365, DFN-529, DHM-25, FT-1518, NSC-765844, omipalisib, OSU-53, OT-043, PQR-514, purinostat mesylate, QR-213, RMC-5552, SN-202, SPR-965, TAM-03, or OSI-027, or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The method of  claim 41  or  42 , wherein the mTOR inhibitor is everolimus, or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The method of any one of  claims 41 - 43 , wherein the mTOR inhibitor is administered at least once daily. 
     
     
         45 . The method of any one of  claims 41 - 44 , wherein the mTOR inhibitor is administered once daily. 
     
     
         46 . The method of any one of  claims 41 - 44 , wherein the mTOR inhibitor is administered twice daily. 
     
     
         47 . The method of any one of  claims 41 - 46 , wherein the mTOR inhibitor is administered orally. 
     
     
         48 . The method of any one of  claims 41 - 47 , wherein the mTOR inhibitor is dosed at about 1 mg to about 1000 mg per administration. 
     
     
         49 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of a pan-HER inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject. 
     
     
         50 . The method of  claim 49 , wherein the pan-HER inhibitor is ZW49, PB 357, MP 0274, VRN 07, BDTX 189, sapitinib, zenocutuzumab, poziotinib, mobocertinib, valitinib, pyrotinib, lapatinib, afatinib, neratinib, or dacomitinib, or a pharmaceutically acceptable salt thereof. 
     
     
         51 . The method of  claim 49  or  50 , wherein the pan-HER inhibitor is sapitinib, zenocutuzumab, poziotinib, mobocertinib, valitinib, pyrotinib, lapatinib, afatinib, neratinib, or dacomitinib, or a pharmaceutically acceptable salt thereof. 
     
     
         52 . The method of any one of  claims 49 - 51 , wherein the pan-HER inhibitor is administered at least once daily. 
     
     
         53 . The method of any one of  claims 49 - 52 , wherein the pan-HER inhibitor is administered once daily. 
     
     
         54 . The method of any one of  claims 49 - 52 , wherein the pan-HER inhibitor is administered twice daily. 
     
     
         55 . The method of any one of  claims 49 - 54 , wherein the pan-HER inhibitor is administered orally. 
     
     
         56 . The method of any one of  claims 49 - 55 , wherein the pan-HER inhibitor is dosed at about 1 mg to about 1000 mg per administration. 
     
     
         57 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an EGFR inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject 
     
     
         58 . The method of  claim 57 , wherein the EGFR inhibitor is doxorubicin+erlotinib, futuximab+modotuximab, abivertinib (e.g., abivertinib maleate), ABP-1119, ABP-1130, afatinib (e.g., afatinib dimaleate), AG-101, AL-6802, almonertinib (e.g., almonertinib mesylate), AM-105, amelimumab, anivantamab, AMX-3009, APL-1898, ASK-120067, AST-2818, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922 BLU-4810, BMX-002, BO-1978, BPI-15086, BP3-7711, brigatinib, C-005, cetuximab, CK-101, CL M-29, CL M-3, CMAB-017, CR-13626, CSHEGF-29, D-0316, D2C7-IT+PVSRIPO, dabrafenib mesylate+panitununab+tramnetinib dimethyl sulfoxide, dacomitinib, DBPR-112, depatuxizumab, DGD-1202, doxitinib (e.g., doxitinib mesylate), DZD-9008, EO-1001, epertinib, erlotinib (e.g., erlotinib hydrochloride), ES-072, FCN-411, FHND-9041, FLAG-001, FLAG-003, FmAb-2, GB-263, GC-1118A, gefitinib, GS-03+Osimertinib, HA-12128, HMPL-309, HMPL-813, HS-627, icotinib (e.g., icotinib hydrochloride), JMT-101, JRF-103, JZB-29, KBP-5209, KNP-501, KU-004, lapatinib (e.g., lapatinib ditosylate), larotinib, lazertinib, lifirafenib (e.g., lifirafenib maleate), MCLA-129, MCLA-158, MDC-22, mobocertinib, mRX-7, MTX-211, MVC-101, naquotinib (e.g., naquotinib mesylate), nazartinib (e.g., nazartinib mesylate), necitumumab, neratinib, nimotuzumab, NRC-2694, NT-004, NT-113, OBX-1012, olmutinib (e.g., olmutinib hydrochloride), osimertinib (e.g., osimertinib mesylate), panitumumab, PB-357, poziotinib, pyrotinib, QL-1105, QL-1203, RXDX-105, SAH-EJ1, sapitinib, SCT-200, selatinib (e.g., selatinib ditosilate), sirotinib, SKLB-1028, SKLB-1206, SPH-118811, SYN-004, TAS-6417, tesevatinib (e.g., tesevatinib tosylate), TGRX-360, tomuzotuximab, TQB-3804, UBP-1215, vandetanib, varlitinib, VRN-071918, VRN-6, WBP-297, WJ-13404, WSD-0922, XZP-5809, yinlitinib, YZJ-0318, ZNE-4, zorifertinib, ZR-2002, ZSP-0391, ORIC-114, DS-2087b, JS-111, LL-191, BI-4020, or BAY-2476568, or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of  claim 57  or  58 , wherein the EGFR inhibitor is afatinib or osimertinib, or a pharmaceutically acceptable salt thereof. 
     
     
         60 . The method of any one of  claims 57 - 59 , wherein the EGFR inhibitor is administered at least once daily. 
     
     
         61 . The method of any one of  claims 57 - 60 , wherein the EGFR inhibitor is administered once daily. 
     
     
         62 . The method of any one of  claims 57 - 60 , wherein the EGFR inhibitor is administered twice daily. 
     
     
         63 . The method of any one of  claims 57 - 62 , wherein the EGFR inhibitor is administered orally. 
     
     
         64 . The method of any one of  claims 57 - 63 , wherein the EGFR inhibitor is dosed at about 1 mg to about 1000 mg per administration. 
     
     
         65 . The method of any one of  claims 1 - 64 , wherein the dual RAF/MEK inhibitor is a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       (I), or a pharmaceutically acceptable salt thereof. 
     
     
         66 . The method of  claim 65 , wherein the dual RAF/MEK inhibitor is a compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         67 . The method of  claim 65 , wherein the dual RAF/MEK inhibitor is a potassium salt of the compound of formula (I). 
     
     
         68 . The method of any one of  claims 1 - 67 , wherein the dual RAF/MEK inhibitor is orally administered to the subject. 
     
     
         69 . The method of any one of  claims 1 - 68 , wherein the dual RAF/MEK inhibitor is administered twice a week. 
     
     
         70 . The method of any one of  claims 1 - 69 , wherein the dual RAF/MEK inhibitor is administered at a dose of 0.5 mg to about 10 mg per administration. 
     
     
         71 . The method of  claim 70 , wherein the dual RAF/MEK inhibitor is dosed at 3.2 mg per administration. 
     
     
         72 . The method of  claim 70 , wherein the dual RAF/MEK inhibitor is dosed at 4 mg per administration. 
     
     
         73 . The method of any one of  claims 1 - 72 , wherein the dual RAF/MEK inhibitor is dosed as a cycle comprising administering the dual RAF/MEK inhibitor for three weeks and then not administering the dual RAF/MEK inhibitor for one week. 
     
     
         74 . The method of any one of  claims 1 - 73 , wherein the cancer is lung adenocarcinoma, non-small cell lung carcinoma, colorectal cancer, uterine endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic type pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, stomach adenocarcinoma, tubular stomach adenocarcinoma, uterine carcinosarcoma, or uterine malignant mixed Mullerian tumor. 
     
     
         75 . The method of any one of  claims 1 - 73 , wherein the cancer is pancreatic cancer, gynecologic cancer (e.g., cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, endometrial cancer, or vulvar cancer), liver cancer, prostate cancer, mesothelioma, breast cancer, bladder cancer, melanoma, lung cancer, colorectal cancer, thyroid cancer, glioblastoma, or renal cancer. 
     
     
         76 . The method of any one of  claims 1 - 73 , wherein the cancer is melanoma, lung cancer, colorectal cancer, ovarian cancer, thyroid cancer, glioblastoma, or renal cancer. 
     
     
         77 . The method of  claim 76 , wherein the lung cancer is non-small cell lung cancer. 
     
     
         78 . The method of  claim 76 , wherein the lung cancer is metastatic non-small cell lung cancer. 
     
     
         79 . The method of  claim 76 , wherein the melanoma is unresectable melanoma. 
     
     
         80 . The method of  claim 76 , wherein the melanoma is metastatic melanoma. 
     
     
         81 . The method of  claim 76 , wherein the cancer is colorectal cancer. 
     
     
         82 . The method of  claim 76 , wherein the cancer is ovarian cancer. 
     
     
         83 . The method of any one of  claims 1 - 82 , wherein the cancer is identified as having a RAS mutation. 
     
     
         84 . The method of any one of  claims 1 - 83 , wherein the cancer is identified as having a KRAS, NRAS, or HRAS mutation. 
     
     
         85 . The method of  claim 84 , wherein the KRAS mutation is a mutation in KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C. 
     
     
         86 . The method of  claim 84 , wherein the KRAS mutation is a mutation in KRAS G13V, KRAS G13D, KRAS G13A, KRAS G13R, KRAS G13S, KRAS G13E, KRAS G12 dup, or KRAS G13C. 
     
     
         87 . The method of  claim 84 , wherein the KRAS mutation is a mutation in KRAS Q61H, KRAS Q61K, KRAS Q61L, KRAS Q61R, KRAS Q61P, or KRAS Q61E. 
     
     
         88 . The method of claim any one of  claims 1 - 87 , wherein the cancer is identified as having RAF mutation. 
     
     
         89 . The method of claim any one of  claims 1 - 88 , wherein the cancer is identified as having a BRAF, ARAF, or CRAF mutation. 
     
     
         90 . The method of  claim 89 , wherein the BRAF mutation is a BRAF V600 mutation. 
     
     
         91 . The method of any one of  claims 1 - 90 , wherein the cancer is identified as having a MEK1 and/or MEK2 mutation. 
     
     
         92 . The method of any one of  claims 1 - 91 , wherein the cancer is identified as having NF1 alterations, KRAS amplification, and/or NRAS amplification. 
     
     
         93 . The method of any one of  claims 1 - 92 , wherein the cancer is identified as having positive phosphor-ERK protein expression (e.g., ≥10%, ≥20%, or ≥30% of cells) detected by immunohistochemistry. 
     
     
         94 . The method of any one of  claims 1 - 93 , wherein the cancer is identified as having a EGFR alteration.